ASCO Guideline Update: Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer

Sentinel Lymph Node Biopsy for Patients With Early-Stage
Breast Cancer: American Society of Clinical Oncology
Clinical Practice Guideline Update
Gary H. Lyman, Sarah Temin, Stephen B. Edge, Lisa A. Newman, Roderick R. Turner, Donald L. Weaver,
Al B. Benson III, Linda D. Bosserman, Harold J. Burstein, Hiram Cody III, James Hayman, Cheryl L. Perkins,
Donald A. Podoloff, and Armando E. Giuliano
Gary H. Lyman, Fred Hutchinson Cancer
Research Center, University of Washing-
ton, Seattle, WA; Sarah Temin, American
Society of Clinical Oncology, Alexandria,
VA; Stephen B. Edge, Baptist Cancer
Center, Memphis, TN; Lisa A. Newman
and James Hayman, University of Michi-
gan, Ann Arbor, MI; Roderick R. Turner,
John Wayne Cancer Institute, Santa Moni-
ca; Linda D. Bosserman, Wilshire Oncology
Medical Group, Rancho Cucamonga;
Armando E. Giuliano, Cedars-Sinai Medical
Center, Los Angeles, CA; Donald L.
Weaver, University of Vermont College of
Medicine and Vermont Cancer Center,
Burlington, VT; Al B. Benson III, Northwest-
ern University, Chicago, IL; Harold
J. Burstein, Dana-Farber Cancer Institute,
Boston, MA; Hiram Cody III, Memorial
Sloan Kettering Cancer Center, New York,
NY; Cheryl L. Perkins, Patient Representa-
tive, Dallas; and Donald A. Podoloff, Univer-
sity of Texas MD Anderson Cancer Center,
Houston, TX.
Published online ahead of print at
www.jco.org on March 24, 2014.
Clinical Practice Guideline Committee
approval: November 19, 2013.
Editor’s note: This American Society of
Clinical Oncology Clinical Practice Guideline
Update provides recommendations with
review and analysis of the relevant litera-
ture for each recommendation. Additional
information, which may include data
supplements, slide sets, patient versions,
clinical tools, and resources, is available at
www.asco.org/guidelines/breastsnb.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: American Soci-
ety of Clinical Oncology, 2318 Mill Rd,
Suite 800, Alexandria, VA 22314;
e-mail: guidelines@asco.org.
© 2014 by American Society of Clinical
Oncology
0732-183X/14/3299-1/$20.00
DOI: 10.1200/JCO.2013.54.1177
A B S T R A C T
Purpose
To provide evidence-based recommendations to practicing oncologists, surgeons, and radiation
therapy clinicians to update the 2005 clinical practice guideline on the use of sentinel node biopsy
(SNB) for patients with early-stage breast cancer.
Methods
The American Society of Clinical Oncology convened an Update Committee of experts in medical
oncology, pathology, radiation oncology, surgical oncology, guideline implementation, and advo-
cacy. A systematic review of the literature was conducted from February 2004 to January 2013 in
Medline. Guideline recommendations were based on the review of the evidence by Up-
date Committee.
Results
This guideline update reflects changes in practice since the 2005 guideline. Nine randomized
clinical trials (RCTs) met systematic review criteria for clinical questions 1 and 2; 13 cohort studies
informed clinical question 3.
Recommendations
Women without sentinel lymph node (SLN) metastases should not receive axillary lymph node
dissection (ALND). Women with one to two metastatic SLNs planning to undergo breast-conserving
surgery with whole-breast radiotherapy should not undergo ALND (in most cases). Women with SLN
metastases who will undergo mastectomy should be offered ALND. These three recommendation are
based on RCTs. Women with operable breast cancer and multicentric tumors, with ductal carcinoma
in situ (DCIS) who will undergo mastectomy, who previously underwent breast and/or axillary surgery,
or who received preoperative/neoadjuvant systemic therapy may be offered SNB. Women who have
large or locally advanced invasive breast cancer (tumor size T3/T4), inflammatory breast cancer, or
DCIS (when breast-conserving surgery is planned) or are pregnant should not undergo SNB. These
recommendations are based on cohort studies and/or informal consensus. In some cases, updated
evidence was insufficient to update previous recommendations.
J Clin Oncol 32. © 2014 by American Society of Clinical Oncology
INTRODUCTION
TheAmericanSocietyofClinicalOncology(ASCO)
first published evidence-based clinical practice
guidelines on use of sentinel node biopsy (SNB) for
patients with early-stage breast cancer in a guideline
published in 2005. At the time of publication, there
was only one published randomized clinical trial
(RCT), by Veronesi et al.1
There were no axillary
recurrences in patients who had tumor-free nodes
and did not undergo axillary lymph node dissection
(ALND),andtheshort-termsurvivalwassimilarfor
those with tumor-free nodes treated with ALND.
However, the study was underpowered for overall
survival(OS).ASCOguidelinesareupdatedatinter-
vals determined by an Update Committee of the
original Expert Panel. Since the publication of the
original guideline, additional randomized trial re-
sults have become available. Practice has changed,
but several issues remain unresolved, especially with
regard to the accuracy of SNB in special circum-
stances.Aformalupdateofthesystematicreviewfor
this guideline and recommendations was con-
ducted. This guideline summarizes the updated lit-
erature search; it also reviews and analyzes new
data regarding the recommendations since the
systematic review for the previous update. Since
2005, ASCO has updated some of its guideline
JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E
© 2014 by American Society of Clinical Oncology 1
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.54.1177The latest version is at
Published Ahead of Print on March 24, 2014 as 10.1200/JCO.2013.54.1177
Copyright 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on March 26, 2014. For personal use only. No other uses without permission.
Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

THE BOTTOM LINE
ASCO GUIDELINE UPDATE
Recommendations for Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: ASCO
Clinical Practice Guideline Update
Guideline Question
● How should the results of sentinel node biopsy (SNB) be used in clinical practice? What is the role of SNB in special circumstances
in clinical practice? What are the potential benefits and harms associated with SNB?
Target Audience
● Medical oncologists, radiation oncologists, pathologists, surgeons, oncology nurses, patients/caregivers, and guideline implementers.
Methods
● A comprehensive systematic review of the literature was conducted, and an Update Committee was convened to review the evi-
dence and develop guideline recommendations. The guide for rating recommendations and strength of evidence is provided in the
Methodology Supplement.
Recommendations
● Recommendation 1: Clinicians should not recommend axillary lymph node dissection (ALND) for women with early-stage breast
cancer who do not have nodal metastases. Type: evidence based; benefits outweigh harms. Evidence quality: high. Strength of rec-
ommendation: strong.
● Recommendation 2.1: Clinicians should not recommend ALND for women with early-stage breast cancer who have one or two
sentinel lymph node metastases and will receive breast-conserving surgery (BCS) with conventionally fractionated whole-breast
radiotherapy. Type: evidence based; benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.
● Recommendation 2.2: Clinicians may offer ALND for women with early-stage breast cancer with nodal metastases found on SNB
who will receive mastectomy. Type: evidence based; benefits outweigh harms. Evidence quality: low. Strength of recommendation:
weak.
● Recommendation 3: Clinicians may offer SNB for women who have operable breast cancer who have the following circumstances:
● 3.1: Multicentric tumors. Type: evidence based; benefits outweigh harms. Evidence quality: intermediate. Strength of recommen-
dation: moderate.
● 3.2: Ductal carcinoma in situ (DCIS) when mastectomy is performed. Type: informal consensus; benefits outweigh harms. Evi-
dence quality: insufficient. Strength of recommendation: weak.
● 3.3: Prior breast and/or axillary surgery. Type: evidence based; benefits outweigh harms. Evidence quality: intermediate. Strength
of recommendation: strong.
● 3.4: Preoperative/neoadjuvant systemic therapy. Type: evidence based; benefits outweigh harms. Evidence quality: intermediate.
Strength of recommendation: moderate.
● Recommendation 4: There are insufficient data to change the 2005 recommendation that clinicians should not perform SNB for
women who have early-stage breast cancer and are in the following circumstances:
● 4.1: Large or locally advanced invasive breast cancers (tumor size T3/T4). Type: informal consensus. Evidence quality: insufficient.
Strength of recommendation: weak.
● 4.2: Inflammatory breast cancer. Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: weak.
● 4.3: DCIS when breast-conserving surgery is planned. Type: informal consensus. Evidence quality: insufficient. Strength of recom-
mendation: strong.
● 4.4: Pregnancy. Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: weak.
Qualifying Statements
● Clinicians may perform SNB for DCIS diagnosed by minimally invasive breast biopsy: one, when mastectomy is planned, because
this precludes subsequent SNB at a second operation; two, when physical examination or imaging shows a mass lesion highly sug-
gestive of invasive cancer; or three, the area of DCIS by imaging is large (Ն 5 cm). SNB may be offered before or after neoadjuvant
systemic therapy (NACT), but the procedure seems less accurate after NACT. This update deleted a recommendation for patients
having undergone prior nononcologic breast surgery or axillary surgery because of insufficient data to inform a recommendation.
(continued on following page)
Lyman et al
2 © 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

methodology, including the phrasing of recommendations, which is
reflected in this document.2
Data Supplement 7 provides both the
2005 and 2013 recommendations.
Positive lymph nodes can contain metastases or be tumor
involved, and the latter terms are more accurate; therefore, this
guideline uses the terms metastasis or metastatic. The term tumor
free is more accurate than the term negative and is therefore used.
In addition, ALND is defined as level I or II axillary dissection.
GUIDELINE QUESTIONS
Overarching Clinical Question
How should the results of SNB be used in clinical practice, and
what are the potential benefits and harms associated with SNB?
Clinical Question 1
Can ALND be avoided in patients who have tumor-free (ie,
negative) findings on SNB?
Clinical Question 2
Is ALND necessary for all patients with metastatic findings
on SNB?
Clinical Question 2.1. For women with metastatic sentinel
lymph nodes (SLNs) planning to undergo breast-conserving surgery
(BCS) with whole-breast radiotherapy?
ClinicalQuestion2.2. Forwomenwithnodalmetastaseswhoare
planning to undergo mastectomy?
Clinical Question 3
What is the role of SNB in special circumstances in clinical prac-
tice (Data Supplement 8)?
METHODS
The recommendations were developed by an Update Committee (Appendix
Table A1, online only) with multidisciplinary representation using a system-
atic review of phase III RCTs, some observational studies, and clinical experi-
ence as a guide. Most of the Clinical Question 1 and 2 recommendations were
evidencebasedandusedpublicationsfoundinaliteraturesearchfrom2004to
January 2013.
The Update Committee only considered observational data for specific
circumstances, and not all of the special circumstances were addressed in this
guideline update. In some selected cases where evidence was lacking, but there
was a high level of agreement among Update Committee members, informal
consensus was used (as noted in the Bottom-Line Box).
Articles were selected for inclusion in the systematic review of the evi-
dence if they met the following criteria:
● Population: women with early-stage breast cancer.
● For Clinical Questions 1 and 2, fully published or recent meeting
presentations of English-language reports of phase III RCTs or rigor-
ously conducted systematic reviews or meta-analyses. Trials with a
population of women with early breast cancer that compared SNB
with the standard treatment of ALND; this included studies compar-
ing SNB alone with SNB plus ALND, for those patients with nega-
tive SLNs.
● For special circumstances, prospective comparative cohort trials were
accepted (criteria listed in Data Supplement 8).
Articles were excluded from the systematic review if they were: (1) meeting
abstracts not subsequently published in peer-reviewed journals; (2) edito-
rials, commentaries, letters, news articles, case reports, or narrative re-
views; and (3) published in a language other than English. The guideline
recommendations were crafted, in part, using Guidelines Into Decision
Support (GLIDES) methodology.2
Ratings for the type and strength of
recommendation, evidence, and potential bias are provided in the Meth-
odology Supplement (www.asco.org/guidelines/breastsnb).
Detailed information about the methods used to develop this guideline
update, regarding the Update Committee composition, guideline develop-
ment process, and steps taken in the systematic review and recommendation
development process, is available in further detail in the Methodology and
Data Supplements at www.asco.org/guidelines/snbbreast.
Guideline Disclaimer
TheClinicalPracticeGuidelinesandotherguidancepublishedhereinare
provided by ASCO to assist providers in clinical decision making. The infor-
mation herein should not be relied on as being complete or accurate, nor
shoulditbeconsideredasinclusiveofallpropertreatmentsormethodsofcare
or as a statement of the standard of care. With the rapid development of
scientificknowledge,newevidencemayemergebetweenthetimeinformation
is developed and when it is published or read. The information is not contin-
ually updated and may not reflect the most recent evidence. The information
addresses only the topics specifically identified therein and is not applicable to
other interventions, diseases, or stages of diseases. This information does not
mandate any particular course of medical care. Furthermore, the information
is not intended to substitute for the independent professional judgment of the
treating provider, because the information does not account for individual
variation among patients. Recommendations reflect high, moderate, or low
confidence that the recommendation reflects the net effect of a given course of
action. The use of words like must, must not, should, and should not indicates
that a course of action is recommended or not recommended for either most
or many patients, but there is latitude for the treating physician to select other
courses of action in individual cases. In all cases, the selected course of action
should be considered by the treating provider in the context of treating the
individual patient. Use of the information is voluntary. ASCO provides this
information on an as-is basis and makes no warranty, express or implied,
regarding the information. ASCO specifically disclaims any warranties of
merchantability or fitness for a particular use or purpose. ASCO assumes no
THE BOTTOM LINE (CONTINUED)
Additional Resources
More information, including a Data Supplement with additional evidence tables, a Methodology Supplement with information about
evidence quality and strength of recommendations, slide sets, and clinical tools and resources, is available at www.asco.org/guidelines/
breastsnb. Patient information is available at www.cancer.net.
SNB in Early-Stage Breast Cancer Update
www.jco.org © 2014 by American Society of Clinical Oncology 3

responsibilityforanyinjuryordamagetopersonsorpropertyarisingoutofor
related to any use of this information or for any errors or omissions.
Guideline and Relationships With Companies
The Update Committee was assembled in accordance with the ASCO
Conflicts of Interest Management Procedures for Clinical Practice Guidelines
(ie, Procedures, summarized at http://www.asco.org/rwc). Members of the
committeecompletedtheASCOdisclosureform,whichrequiresdisclosureof
financial and other interests that are relevant to the subject matter of the
guideline,includingrelationshipswithcommercialentitiesthatarereasonably
likely to experience direct regulatory or commercial impact as a result of
promulgation of the guideline. Categories for disclosure include employment
relationships, consulting arrangements, stock ownership, honoraria, research
funding, and expert testimony. In accordance with the Procedures, the major-
ity of the members of the committee did not disclose any such relationships.
RESULTS
AssummarizedinTable1andDataSupplement1(Tables1Aand2A),
a total of nine RCTs were deemed eligible for inclusion in the system-
atic review of the evidence for Clinical Questions 1 and 2; 13 cohort
studies were deemed eligible for Clinical Question 3, as presented in
Data Supplements 1 and 2 (Tables 1B, 2B, and 3). No phase II studies,
meta-analyses, or other systematic reviews were found that met the
ASCOsystematicreviewcriteriaforthisguideline(DataSupplement8
addresses special circumstances). These studies comprise the eviden-
tiary basis of the guideline recommendations. The identified trials
were published between 2004 and 2013. The randomized trials com-
paredsimilarinterventions.Theprimaryoutcomeforfourofthetrials
for Clinical Question 1 was therapeutic efficacy,3,6,9,13
as it was in two
of the trials for Clinical Question 2.4,12
Morbidities and quality of life
(QOL) were the primary outcomes for the three other studies,5,7,8,11
althoughtheywereframedinavarietyofways,suchasrecurrence-free
survival, event-free survival (EFS), all-cause mortality, and so on. The
cohort studies for Clinical Question 3 reported a mix of efficacy and
adverse effect–related outcomes (Data Supplement 2). Characteristics
of the study participants are listed in Data Supplement 1 (Tables 2A
and 2B).
Study Quality
AssummarizedinTable2,studyqualitywasformallyassessedfor
the nine RCTs identified. Design aspects related to individual study
quality were assessed by one reviewer, with factors such as blinding,
allocation concealment, placebo control, intention to treat, funding
sources,andsoon,generallyindicatingalowtointermediatepotential
risk of bias for most of the identified evidence. Follow-up times varied
among studies, lowering the comparability of the results. The Meth-
odology Supplement provides for definitions of ratings for overall
potential risk of bias.
Outcomes and Adverse Events
Dataonkeyoutcomesofinterestandkeyadverseeventsarelisted
in Table 1 (RCTs) and in Data Supplement 2 (cohort studies).
OVERARCHING CLINICAL QUESTION
How should the results of SNB be used in clinical practice?
NineRCTswerefoundtoinformthisrecommendation.Noneof
the trials showed any difference in mortality among participants who
underwent ALND or SNB for either those with lymph node metasta-
ses or tumor-free (negative) SLNs. One trial showed statistically sig-
nificant longer disease-free survival (DFS)12
with SNB, and one trial
showed a statistically significant noninferiority outcome in deaths in
those with metastatic nodes who did not undergo ALND.4
Clinical
Question 2 is divided into two subquestions for women with SLN
metastases compared with tumor-free nodes.
CLINICAL QUESTION 1
Can ALND be avoided in patients who have tumor-free (negative)
SLNs?
RECOMMENDATION 1
Clinicians should not recommend ALND for women with early-
stage breast cancer who do not have nodal metastases. Type: evidence
based; benefits outweigh harms. Evidence quality: strong. Strength of
recommendation: high.
Literature Review and Analysis
Seven RCTs have been published since the previous version of
this guideline15
that prospectively investigated whether ALND can be
avoidedinpatientswhohavetumor-freefindingsonSNB.Thesetrials
include: NSABP (National Surgical Adjuvant Breast and Bowel Proj-
ect) B32,13,14,16,17
ALMANAC (Axillary Lymphatic Mapping Against
Nodal Axillary Clearance),5,18,19
Sentinella/GIVOM (Gruppo Inter-
disciplinare Veneto di Oncologia Mammaria),6,20,21
Canavese et al,3
RACS (Royal Australasian College of Surgeons)/SNAC (Sentinel
Node Versus Axillary Clearance),7,8,22,23
NCT00970983,9,10
and the
Cambridge/East Anglia Study Group.11
NSABP B32 produced four
publications that met the systematic review selection criteria. These
publications included results on OS, recurrence, adverse events, tech-
nicalsuccess,andperformance.TheALMANACstudypublishedfour
articles, which reported morbidities, QOL, recurrence, and perfor-
mance. Three reports from Sentinella/GIVOM published results on
morbidities, recurrence, OS/mortality, DFS, performance, adverse
events, and QOL. Canavese et al published one article that reported
recurrence, OS/mortality, EFS, morbidities, and false-negative rates
(FNRs). The RACS/SNAC study was published in four reports on an
interim analysis of the first 150 participants; results included morbid-
ities, QOL, and FNRs. For NCT00970983, there were two articles,
reporting recurrence, mortality/OS, DFS, and performance. The
Cambridge/East Anglia Study Group published one article reporting
on morbidities and QOL. (The IBCSG [International Breast Cancer
Study Group] 23-01 is discussed under Clinical Question 2 because
most of the patients had one to three micrometastases.)
Clinical Outcomes
This section summarizes the efficacy results from the trials pub-
lishedsincethesystematicreviewforthe2005guidelineforthisclinical
question. Five trials reported results on clinical/efficacy out-
comes.3,5,6,9,13
In four of those five trials, survival outcomes were the
primary end points.3,6,9,13
Of these four trials, NSABP B32 had the
largest number of participants (N ϭ 3,989). The second largest, Sen-
tinella/GIVOM,had697participants,buttheauthorsofthisstudyfelt
it was too small to draw conclusions.
Lyman et al

Table1.RCTs:Outcomes
StudyComparisons
No.ofPatients
Evaluatedor
Randomly
Assigned‫ء‬
Median
Follow-UpRecurrenceOS/MortalityQOLandAdverseEventsFNR,NPV,andPPV
Overall
Accuracy
Canaveseetal3
(2009)
SNBϩALND110of1245.5years5-yearEFS(includingrecurrence),94.5%;
95%CI,90.9to98.1;Pϭ.72
Annualrateofevents:16.2per1,000†
OS,97.2%;95%
CI,95.4%to
98.9%
NRFNR(ALND),6.84%93%
SNBϩALND
(ifSLN
positive)
115of1245-yearEFS(includingrecurrence),89.8%;
95%CI,86.9to92.7;Pϭ.72
OS,97.2%;95%
CI,95.4%to
98.9%
NPV,91.1%
Annualrateofevents,18.6per1,000†Pϭ.07PPV,71.1%
Noaxillary
RRofSNBvSNBϩALND,0.87;95%
CI,0.38to2.01;Pϭ.741
Giulianoetal4
(2011;
ACOSOG
Z0011)
SNBalone436of4466.3years5-yearDFS,83.9%;95%CI,80.2%to
87.9%
5-yeardeaths,42
of426
QOLNR
HigherforALNDthanSLND-alonegroup(70%v25%;
PϽ.001)
LymphedemainALNDgroupsignificantlymorecommon
bysubjectivereport(PϽ.001)andbyobjective
assessmentofarmcircumference
NRNR
5-yearLR,1.6%;95%CI,0.7%to3.3%
5-yearLRR-freesurvival,96.7%;95%CI,
94.7%to98.6%;Pϭ.28
5-yearOS,92.5%;
95%CI,90.0%
to95.1%;Pϭ
.008
SNBϩALND420of4455-yearDFS,82.2%;95%CI,78.3%to
86.3%
5-yeardeaths,52
of445
5-yearLR,3.1%;95%CI,1.7%to5.2%5-yearOS,91.5%;
95%CI,89.1%
to94.5%
5-yearLRR-freesurvival,95.7%;95%CI,
93.6%to97.9%;Pϭ.28
HR,0.79;90%CI,
0.56to0.10‡
DFS:HR,0.82;95%CI,0.58to1.17‡
HR,0.88;95%CI,0.62to1.25§
HR,0.87;90%CI,
0.62to1.23§
Manseletal5
(2006;
ALMANAC
trial)
SNBonly495of47812monthsAxillary,1At12months,
sevendeaths
(twobreast
cancerspecific)
SNBgroup:overallpatient-recordedQOLstatistically
significantlybetter(PՅ.003)ʈ¶
FNR,6.7%;19of
282
97.6%;782of
803
ALNDonly476of496Axillary,4At12months,
sevendeaths
(twobreast
cancerspecific)
SNBgroup:overallpatient-recordedQOL;TOI:1month
aftersurgery,PϽ.001;3,6,and12monthsafter
surgery,Pϭ.001
NPV,NR
Difference,2.7%;95%CI,Ϫ1.5%to
7.8%
SNBgroup:FACT-Bϩ4:changeinscorefrombaselineto
1(PϽ.001),3(Pϭ.001),6(Pϭ.003),12(Pϭ
.002),and18months(Pϭ.003)
ArmfunctioningdeteriorationgreaterinALNDthanin
SNBgroupateachstudytimepoint(PϽ.001)
Moderateorseverelymphedemareportedmoreoften
bypatientsinALNDthaninSNBgroupat1,3,6,and
12monthsaftersurgery(eg,5%v13%at12
months;PϽ.001)
RR,0.37(95%CI,0.23to0.60)at12monthsfor
lymphedemaforSNBcomparedwithALNDgroup
PPV,NR
(continuedonfollowingpage)

Table1.RCTs:Outcomes(continued)
StudyComparisons
No.ofPatients
Evaluatedor
Randomly
Assigned‫ء‬
Median
Overall
Accuracy
SNBgroup:meanchangeinarmvolumeat12months,
1.028;95%CI,1.016to1.039
ALNDgroup:meanchangeinarmvolumeat12months,
1.028;95%CI,1.016to1.039
Lymphedema:SNBvALND:RR,0.37;95%CI,0.23to
0.60;absoluterate,5%v13%
Sensoryloss:SNBvALND:RR,0.37;95%CI,0.27to
0.50;absoluterate,11%v31%;PϽ.001
HigherrateofsensorydeficitinALNDvSNBgroup(by
self-assessment,at12months),31%v11%;percent
ofpatientswhohadՆonearmproblem1month
postsurgerygreaterinSNBvALNDgroup
RR,0.37;95%CI,0.27to0.50;sensorydeficitat12
monthsinfavorofSNBgroup
ICBNnervedividedin22.6%(88of390)ofALNDv
5.3%(21of400)ofSNBgroup(PϽ.001)
SNBgroup:drainusage,lengthofhospitalstay,andtimeto
resumptionofnormalday-to-dayactivitiesaftersurgery
werestatisticallysignificantlylower(PϽ.001)
SNBgroup:axillaryoperativetimereduced(Pϭ.055)
Zavagnoetal6
(2008;
Sentinella/GIVOM)
SNBϩALND34556months5-yearDFS,87.6%;95%CI,83.3to90.95-yearOS,95.5%;
95%CI,92.2
to97.5
SF-36andPGWB:nosignificantdifferencesbetween
groupsafter24months
FNR,16.7%(18of
108);95%CI,
10.2to25.1
94.4%(305of
323);95%CI,
91.3to96.7
Distant,11of345
LRR,16of345
Contralateral,2of345
Deathresulting
fromnon-BC
causes,11of
345
Lymphedema(SNB/ALND):meanOR,0.48;95%CI,0.3
to0.8;Pϭ.01
PPV,NR
NPV,92.3%(215of
233);95%CI,
88.1to95.4
SNBϩALND
(ifSLN
positive)
3525-yearDFS,89.9%;95%CI,85.3to
93.1;Pϭ.769
5-yearOS,94.8%;
95%CI,91.6
to96.8
Numbness(SNB/ALND):meanOR,0.51;95%CI,0.4to
0.7;PϽ.001
Distant,16of352
LRR,3of352
Deathresulting
fromnon-BC
causes,6of
352
Shoulderpain(SNB/ALND):meanOR,0.74;95%CI,0.5
to1.1;Pϭ.11
Restrictionsofshouldermobility(SNB/ALND):meanOR,
0.55;95%CI,0.3to0.9;Pϭ.016
Smithetal7
(2009),
Ungetal8
(2004;RACS/
SNAC)
ALND319NRNRNRNRFNR,5%(interim)NR
SNBϩALND
(ifSLN
positive)
324Armvolume:
Clinician:4.4%increaseinALND;2.9%increaseinSNB
Patient:9.5%increaseinALND;4.1%increaseinSNB
Axillaryclearance:
Clinicianrating:routineaxillaryclearance:mean,4.4;SE,
0.4;SLN-basedmanagement:mean,2.9;SE,0.4;
meandifferencebetweengroups:mean,1.5;SE,0.6;
MWW,PϽ.001
Patientreport:routineaxillaryclearance:mean,4.4;SE,
0.4;SLN-basedmanagement:mean,2.9;SE,0.4);
Meandifferencebetweengroups:mean,1.5;SE,0.6;
MWW,PϽ.001
NPV,98%(interim)
PPV,95%(interim)
Lyman et al

StudyComparisons
No.ofPatients
Evaluatedor
Randomly
Assigned‫ء‬
Median
Overall
Accuracy
Veronesietal9,10
(2010;
NCT00970983)
SNBϩALND257102
months
10-yearEFS,88.8%;95%CI,84.6to
92.6
OS,89.7%;95%
CI,85.5to
93.8;Pϭ.15
NRFNR,8%;95%CI,
3to15
5-yearDFS,89.9%;95%CI,85.3to
93.1;Pϭ.769
Deaths(BC),14of
257
Distant,20of257
LRR,4of257
Superclavian,2of257
Deaths(non-BC),
9of257
SNBϩALND
(ifSLN
positive)
25910-yearEFS,89.9%;95%CI,85.9to
83.9
OS,93.5%;95%
CI,90.3to
96.8;Pϭ.15
5-yearDFS,89.9%;95%CI,85.3to
93.1;Pϭ.769
Deaths(BC),11of
259
Distant,17of259
LRR,4of259
Axillary,2of259
Deaths(non-BC),
4of259
Purushothametal11
(2005;
Cambridge/
EastAnglia
StudyGroup)
SNBalone
(SLN
negative)
8612monthsNRNRSF-36:meandifference,3.7;95%CI,1.2to6.1;
Pϭ.001
NRNR
SNBϩALND
(control)
155;144of
155
underwent
follow-up
InSNBϩALND(ifSLNpositive)group:
Physicalfunctioningscore,3.2;95%CI,1.1to5.4;Pϭ
.003(higher)
Vitalityscore,3.7;95%CI,1.1to6.2;Pϭ.004(higher)
SNBϩALND
(ifSLN
positive)
143;57of143
comprised
control
group;139
of143
underwent
follow-up
GSIscale:somatizationlower(Pϭ.001)
MACscale:NS
Depressionandanxiety:NSʈ
Lymphedema:meanOR,0.30;95%CI,0.18to0.68;
Pϭ.004
Differenceinarmvolumechange:mean,35.4mL;SE,
12.2;Pϭ.004
Neurologic/sensorydeficits:overallfewersensory
findingswithSNBϩALND;PϽ.001
Shoulderimpairment:reductioninmobilityalwayslower
onaverageinstudygroup(lessimpairment);
significantonlyforflexion(Pϭ.04)

StudyComparisons
No.ofPatients
Evaluatedor
Randomly
Assigned‫ء‬
Median
Overall
Accuracy
Galimbertietal12
(2013;IBCSG
23-01)
ALNDonly
(afterSNB)
4645.0yearsDFS,84.4%;95%CI,80.7to88.1;
Pϭ.0042
5-yearOS,97.5%;
95%CI,96.0
to99.2
QOLNR
Lymphedema:ALND,13%(59of464);noALND,15%
(15of467);PϽ.001
Sensoryneuropathy:ALND,18%(82of463);noALND,
12%(55of467);Pϭ.012
Motorneuropathy:ALND,8%(37of464);noALND,3%
(13of467);PϽ.001
Infections:ALND,1of464
Patientswithreportedlong-termsurgicalevents(grade
3-4)includedonesensoryneuropathy(grade3),three
lymphoedema(twograde3andonegrade4),and
threemotorneuropathy(grade3),allingroup
undergoingALND,andonegrade3motorneuropathy
ingroupwithoutALND;oneseriousadverseevent
wasreported:postoperativeinfectioninaxillaingroup
withALND
NRNR
LR,10of464
LRR,11of464
Regional,1of464
Distant,34of464
Axillary,1of464
All-cause
mortality/deaths,
4%(19of464)
NoALND
(afterSNB)
467DFS,87.8%;95%CI,84.4to91.2;
Pϭ.0042
5-yearOS,97.5%;
95%CI,95.8
to99.1
LRR,13of467
LR,8of467
Regional,5of467
Distant,25of467
Axillary,4of467
All-cause
mortality/deaths,
4%(17of467)
HR,0.78;95%CI,0.55to1.11;
Pϭ.0042(noALNDvALND)
HR,0.89;90%CI,
0.52to1.54;
Pϭ.73
Lyman et al

StudyComparisons
No.ofPatients
Evaluatedor
Randomly
Assigned‫ء‬
Median
Overall
Accuracy
Kragetal13,14
(2010;NSABP
B32;interim
report,nϭ
150)
SNBalone(if
SLN
negative)
2,01195.6
months
(mean)
Totalevents,16.7%;336of2,011events8-yrOS,90.3%;
95%CI,88.9
to91.8
QOLNR
Allergicreaction,8%(bluedye)
ShoulderabductiondeﬁcitsՆ10%peakedat1weekfor
SNBϩALND(75%)andSNB(41%)groups
ArmvolumedifferencesՆ10%at36monthswere
evidentforSNBϩALND(14%)andSNB(8%)groups
Numbnessandtinglingpeakedat6monthsforSNBϩ
ALND(49%and23%)andSNB(15%and10%)
groups
FNR,38.6%(268of
694);95%CI,
35.0to42.4
97.1%(2,544of
2,619);95%
CI,96.4%to
97.7%(of75
patientswith
negativeSNB
withnode-
positive
ALND)
DFS,16.7%;336of2,011HR,1.19;95%CI,
0.95to1.49;
Pϭ.13†
NPV,9.8%(75of
766);95%CI,
7.8to12.1
Distant,3.2%;64of2,011PPV,NR
LR,2.4%;49of2011
Regionalnode,0.7%;14of2,011EFS,83.3%;
1,675of2,011
Contralateral,2.2%;44of2,011Deaths,8.4%;169
of2,011
Deaths(noBC),
2.8%;56of
1,975
SNBϩALND1,975Totalevents,16%;315of1,9758-yearOS,91.8%;
95%CI,90.4
to93.3†
DFS,315of1,975
Distant,2.8%;55of1,975
LR,2.7%;54of1,975
HR,1.20;95%CI,
0.96to1.50;
Pϭ.12†
Regionalnode,0.4%;8of1,975
Contralateral,2.8%;56of1,975EFS,84.1%;
1,660of1,975
Deaths,7%;140
of1,975
Deaths(noBC),
2.3%;5of
1975
Abbreviations:ACOSOG,AmericanCollegeofSurgeons;ALMANAC,AxillaryLymphaticMappingAgainstNodalAxillaryClearance;ALND,axillarylymphnodedissection;BC,breastcancer;DFS,disease-free
survival;EFS,event-freesurvival;FACT-Bϩ4,FunctionalAssessmentofCancerTherapy–Breast,scaleversion4;FNR,false-negativerate;GIVOM,GruppoInterdisciplinareVenetodiOncologiaMammaria;GSI,
GlobalSeverityIndex;HR,hazardratio;IBCSG,InternationalBreastCancerStudyGroup;LR,localrecurrence;LRR,locoregionalrecurrence;MAC,MentalAdjustmenttoCancer;NPV,negativepredictivevalue;
NR,notreported;NS,notsigniﬁcant;NSABP,NationalSurgicalAdjuvantBreastandBowelProject;OR,oddsratio;OS,overallsurvival;PGWB,PsychologicalGeneralWellBeingIndex;PPV,positivepredictive
value;QOL,qualityoflife;RACS,RoyalAustralasianCollegeofSurgeons;RCT,randomizedcontrolledtrial;RR,riskratio;SF-36,ShortForm36;SLN,sentinellymphnode;SNAC,SentinelNodeVersusAxillary
Clearance;SNB,sentinelnodebiopsy;TOI,TrialOutcomesIndex.
‫ء‬
Evaluatedand/orrandomlyassignedwithfollow-up.
†Includesdeaths.
‡UnadjustedHR.
§AdjustedHRforadjuvanttherapy(chemotherapy,endocrinetherapy,and/orradiationtherapy)andage.
ʈBeckDepressionInventory.
¶State-TraitAnxietyInventory
#EuropeanOrganisationforResearchandTreatmentofCancerBreastCancerModule(EORTC-QLMBR23).

Table2.RCTs:QualityAssessment
Study
Adequate
Randomization
Concealed
Allocation
Sufficient
Sample
Size
Comparable
GroupsBlinded
Validatedand
ReliableMeasures
Adequate
Follow-Up
Insignificant
COIs
OverallRisk
ofBias
Canaveseetal3
(2009)X?—X—X???
Giulianoetal4
(2011;ACOSOGZ0011)??XXPartiallyX?XLow
Manseletal5
(2006;ALMANACtrial)XXXX—PartiallyXX?
Zavagnoetal6
(2008;Sentinella/GIVOM)XPartiallyXX—Partially?XLow
Smithetal7
(2009)?—XX—X?XIntermediate‫ء‬
Smithetal7
(2009),Ungetal8
(2004;
RACS/SNAC)
??X?Partially—†?X?
Veronesietal9,10
(2010;NCT00970983)XXXX—X?,partiallyXLow
Purushothametal11
(2005;Cambridge/EastAnglia
StudyGroup)
XXXXPartially;wasnot
doubleblind
XXXLow
Galimbertietal12
(2013;IBCSG23-01)X?PartialX—XXXIntermediate
Kragetal13,14
(2010;NSABPB32)‡X??X?XXNotrelevantLow
NOTE.Xindicatescriterionwasmet;—indicatescriterionwasnotmet;?indicatesinsufficientdetail,notreported,and/oruncertainriskofbias.
Abbreviations:ACOSOG,AmericanCollegeofSurgeons;ALMANAC,AxillaryLymphaticMappingAgainstNodalAxillaryClearance;COI,conflictofinterest;GIVOM,GruppoInterdisciplinareVenetodiOncologia
Mammaria;IBCSG,InternationalBreastCancerStudyGroup;NSABP,NationalSurgicalAdjuvantBreastandBowelProject;RACS,RoyalAustralasianCollegeofSurgeons;RCT,randomizedcontrolledtrial;SNAC,
SentinelNodeVersusAxillaryClearance.
‫ء‬
Severalitemswerenotreported;trialnotfullypublished.
†Interimanalysis.
‡Interimpublication(nϭ150).
Lyman et al

Survival/mortality. Of the five trials reporting OS and/or mor-
tality, none of the studies reported statistically significant differ-
ences.3,6,5,9,16
For example, the largest study13
reported an actuarial
8-year survival rate for SNB and ALND of 91.8% (95% CI, 90.4 to
93.3), compared with 90.3% (95% CI, 88.8 to 91.8) for SNB alone.
All-cause mortality was 4% in each arm.16
DFS/EFS. Of the four trials reporting DFS and/or EFS, none
reported statistically significant differences.3,6,9,16
Recurrence. Five trials reported on recurrence.3,5,6,9,16
They
found that the rates of in-breast local recurrence, axillary recur-
rence, and distant recurrence were similar with SNB alone and with
SNB plus ALND. For example, Canavese et al3
showed the overall
annual rate of events per 1,000 (including deaths) was 16.2 with
SNB and 18.6 with ALND. In NSABP B32, with locoregional recur-
rence as the first event, local recurrence was 2% in both arms, and
distant recurrence was similar.
Adverseevents. Five trials reported adverse events.5-8,11,18,20
In
most studies, results of adverse events/effects were higher for those
with tumor-free SLNs who underwent ALND than for those who
underwent only SNB. Important adverse effects included
lymphedema, infections, seroma, and neurologic and sensory def-
icits, including paresthesia and shoulder pain and/or impairment
of motion.
In the four studies reporting lymphedema, a clinically important
adverse event, lymphedema was clearly identified to occur even with
SNB alone but at lower rates than those found among patients under-
going ALND. In the ALMANAC trial, lymphedema was measured by
participant self-assessment and reported as moderate or severe at 12
months in 1% with SNB versus 2% with ALND (P Ͻ .001).5
In
another study, lymphedema was statistically significantly lower with-
out ALND.6
The NSABP B32 study assessed lymphedema by mea-
surement of arm volume Ն a 10% difference from baseline. Grade 3
and 4 rates of lymphedema were not notably different. Overall
lymphedema was higher in ALND arm.24
Another set of adverse events reported in several studies
were neurologic/sensory deficits. In the four studies reporting
these,5,6,11,13,20,21
the percentages of patients experiencing these
deficits were statistically significantly lower in the SNB-alone
arms.5,6,11,18,20
Forexample,residualarmtinglingandnumbnessat36
months were significantly lower in favor of SNB. Rates of sensory and
motor neuropathy in NSABP B32 were higher with ALND. In some
serious adverse-event categories, there were no significant differences.
For example, in one study, seroma was stratified by nodal status, and
the proportion of patients who developed a seroma with SNB was
significantly smaller than the proportion in the SNB plus ALND
control group; the difference in those requiring aspirations was also
significant.11
InNSABPB32,therewasnotadifferenceinthepercent-
age of patients who had grade Ն 3 surgery-related events.
Other Outcomes
Performance. Six of the trials to date have reported on perfor-
mance aspects of SNB.3,5-9,16
Performance outcomes extracted in the
systematic review include FNR, negative predictive value (NPV), and
overall accuracy. FNRs reported in the six studies ranged from ap-
proximately 4.6%9
(ASCO staff calculation) to 16.7%.6
Three studies
reported NPVs ranging from 90.1%3
to 96.1%.6,16
Four studies re-
ported overall accuracy of SNB results ranging from 93%3
to 97.6%.6,16,19
QOL. Three studies reported on QOL.5,11,18,20
The trials used
such instruments as the Trial Outcome Index (TOI), Functional As-
sessment of Cancer Therapy–Breast, scale version 4 (FACT-Bϩ4),
Psychological General Well Being Index (PGWB), Short Form–36
(SF-36), and the simple visual analog QOL, as well as tools for mea-
suring psychological morbidity. Either there were no significant dif-
ferences, or results favored the SNB-alone arm. For example, in the
ALMANAC trial, there were statistically significantly better outcomes
for participants in the SNB-alone arm; also reported were changes in
FACT-Bϩ4 scores favoring SNB alone.18
Clinical Interpretation
The Z0010 study25
was not included in final systematic review,
because it was a prospective multicenter cohort, not an RCT. Its
primary end point was OS, and secondary end points included DFS
and axillary recurrence; however, they were not reported in the Z0010
publication used in this guideline.25
The study also measured adverse
events at 30 days and at 6-month intervals up to year 3 and annually
thereafter.Atotalof5,539patientswereenrolled,andtherewere5,327
available for analysis. In a multivariable analysis, age (at a cutoff of 70
years) was a predictor for axillary seroma. In another outcome of a
multivariableanalysis,decreasingagewasassociatedwiththepresence
of paresthesia.
CLINICAL QUESTION 2
Is ALND necessary for all patients with metastatic findings on SNB?
This section summarizes the efficacy results from the trials pub-
lishedsincethesystematicreviewforthe2005guidelineforthisclinical
question. It is based on two RCTs that both reported efficacy and
adverse-event results in patients with metastases in SLNs randomly
assigned to either completion ALND or no ALND: ACOSOG (Amer-
ican College of Surgeons Oncology Group) Z00114
and IBCSG 23-
01.12
The ACOSOG Z0011 investigators reported on recurrence, OS/
mortality, DFS, and adverse events in four articles included in this
systematic review. The IBCSG 23-01 investigators reported on recur-
rence, OS/mortality, DFS, and adverse events in one article published
aftertheASCOsystematicreview,buttheUpdateCommitteedeemed
it appropriate to include because of its confirmatory nature.
ACOSOGZ0011wasanoninferiorityRCTinwhich446patients
wererandomlyassignedtoSNBwithnofurtheraxillarytreatmentand
445 to SNB plus ALND. All patients had metastatic SLNs, and all had
T1 or T2 tumors managed by lumpectomy and planned whole-breast
irradiation. The extent of node involvement was micrometastatic
(metastaticfocusϽ2mm)inapproximatelyhalfofthestudypatients,
but this information was not available for all trial participants. OS was
the primary outcome. The primary outcome of IBCSG 23-01 was
noninferiority in DFS, and this study was designed for patients with
sentinel node micrometastases. It had a sample size of 964 partici-
pants; most participants had only one metastatic node. Consistent
with the study design, 98% of the SLN tumors in both randomized
arms had micrometastatic disease only. Results in IBCSG 23-01 were
not analyzed by size of metastases. More than 80% of the participants
intheACOSOGZ0011andIBCSG23-01trialshadestrogenreceptor–
positive disease. Both of these studies were closed early because of
failure to meet their accrual targets.

The recommendations in response to this clinical question were
split into two separate recommendations. The first recommendation
was crafted to reflect the eligibility criteria of Z0011 (women with
early-stage breast cancer and one to two SLN metastases, who under-
went BCS with whole-breast radiotherapy).
CLINICAL QUESTION 2.1
Is ALND necessary for all patients with metastatic findings on SNB
planning to undergo BCS with whole-breast radiotherapy?
RECOMMENDATION 2.1
Clinicians should not recommend ALND for women with early-
stage breast cancer and one or two SLN metastases who will undergo
BCS with conventionally fractionated whole-breast radiotherapy.
Type: evidence based; benefits outweigh harms. Evidence quality:
strong. Strength of recommendation: high.
Literature Review and Analysis: Clinical Outcomes
Mortality. There was no apparent negative impact on mortality
of omitting ALND (there was a statistically significant difference for
noninferiorityinmortality)afteramedianfollow-upof6.3years.This
wasthefirstRCTtoshowtheseresults.Therewerenosuchdifferences
in IBCSG 23-01.
DFS. In Z0011, DFS was not statistically significant between
arms. In IBCSG 23-01, there was a 3.4% reduction in DFS for SNB
alone, which was statistically significant for noninferiority for
ALND, with a 5-year follow-up. The per-protocol assessment of
DFS was also statistically significant for noninferiority (P ϭ .0073).
However, this study randomly assigned only 934 of an accrual
target of 1,960 participants.12
Recurrence. Both studies reported on recurrence. In locore-
gional, axillary, or distant recurrence, outcome results showed no
significant differences.4
The differences were not statistically signifi-
cant between arms in IBCSG 23-01 (eg, local recurrence rate at first
event was 2% in both arms; distant recurrence was 7% for ALND and
5% for no ALND).12
Adverse events. There were statistically significant differences in
rates of adverse events between study arms in both studies. Using
slightly different numbers in the denominator than in the primary
report extracted, another ACOSOG Z0011 publication reported on
surgical complications. The protocol did not include objective mea-
surements of arm volume. However, subjectively reported
lymphedema was higher with ALND than in those with SNB alone. It
was statistically significantly higher starting at 12 months, although
not at 6 months or by arm measurement.26
There was statistically
significantly higher axillary seroma and parethesia in the immediate
ALND arm (P Ͻ .001), but not impaired range of movement (the
latter two at 1 year), in a joint analysis of the cohort study Z0010 and
RCT Z0011.27
In a third-line report from Z0011, adverse surgical
effects were 45% less in the SNB arm, including lymphedema Ն 12
months.4,26,27
InfectioninZ011wasreportedaslowerwithSNBalone
(P ϭ .0026).26
In IBCSG 23-01, there were lower overall rates of lymphedema
(13% v 3%; P Յ .001) with no ALND. The percentages of patients
experiencing neurologic/sensory deficits were also reported as higher
withALND(eg,motorneuropathy);however,theratesofgrade3to4
deficitswerelowinIBCSG23-01.12
Itisimportanttonotethatadverse
eventswerenotstratifiedbymicro-versusmacrometastasesinIBCSG
23-01. Infection was higher in the ALND arm (P ϭ .0016) in Z0011;
there was one case of infection in the ALND arm of IBCSG 23-01.
There was not a subgroup of analyses of those whose SLN tumors
were Ն 2 mm in IBCSG 23-01 (2% in each arm).
Other Findings
Performance and QOL. There are not yet reports of findings on
performance or QOL to inform this recommendation.
TheeligibilitycriteriaforZ0011includedafindingofametastatic
SLNbyfrozensection,touchpreparation,orhematoxylin-eosin(HE)
staining; all participants had lumpectomies. Exclusion criteria in-
cluded having Ն three metastatic SLNs. Most patients entered the
study after undergoing SNB, but 287 of 891 had not yet undergone
SNB and were randomly assigned after surgeons found metastatic
SLNsintraoperatively.4
ThegroupwithՆthreemetastaticSLNscom-
prised 21% of the patients in the ALND arm and 3.7% in the SNB-
alone arm; there was a higher proportion of patients with zero to two
metastatic nodes in the SNB-alone arm. Although this was set an as
ineligibility criterion, some of the patients were enrolled before nodal
status was known; if it turned out they had Ն three SLNs, these
patients were included in the analysis.
By contrast, in IBCSG 23-01, Ͻ 1% of those in the ALND arm
andnoparticipantintheno-ALNDarmhadՆthreemetastaticSLNs.
According to the original eligibility criteria, participants could have
only one micrometastatic SLN. The criteria for eligibility were broad-
ened after the study began to include patients with Ն one metastatic
SLN, with multicentric or multifocal tumors (formerly only unicen-
tric),andwhoselargestlesionsizewasՅ5cm(formerlyՅ3cm).Five
percent of participants undergoing ALND and 4% of those randomly
assigned to no ALND had two metastatic SLNs. Most of the partici-
pants had one metastatic node; however, 98% of the SLN tumors in
both arms were Յ 2 mm (micrometastatic).
In the expert opinion of the Update Committee, ALND can be
avoided in cases of BCS, but only when conventionally fractionated
whole-breast radiation therapy is planned. Although there were pa-
tients in the IBCSG study in the group managed without axillary
dissectionwhounderwentBCSwithnoradiationtherapy(12patients;
3%) or intraoperative partial-breast irradiation (80 patients; 19%),
these subgroups were deemed too small to influence the decision by
the Update Committee not to extend the recommendation beyond
patients treated with conventionally fractionated whole-breast irradi-
ation. This recommendation does not apply to patients whose axillary
nodal positivity is documented by axillary fine-needle aspiration
(FNA); clinicians may still perform SNB if the abnormal lymph node
is removed. Data are insufficient to address whether FNA-positive
patients can undergo SNB (under the assumption that resected SLNs
represent the FNA-biopsied node) and then avoid ALND after resec-
tion of the metastatic SLN. Patients with FNA-positive nodes may
haveahigheraxillarytumorburdencomparedwiththosewithdisease
apparent on dissection of an SLN.
Clinicians may also consider this recommendation with caution
in cases of women with large or bulky metastatic axillary SLNs and/or
those with gross extranodal extension of the tumor. These were exclu-
sion criteria for Z0011. The former were represented by few patient
Lyman et al

cases in the ACOSOG Z0011 study, and the latter were specifically
excluded. These uncommon patient cases may or may not carry a
higher risk of axillary recurrence than those largely represented in
the trial.
CLINICAL QUESTION 2.2
Is ALND necessary for all patients with metastatic findings on
SNB who are planning to undergo mastectomy?
RECOMMENDATION 2.2
Clinicians may offer ALND for women with early-stage breast
cancer with nodal metastases found on SNB who will undergo mas-
tectomy. Type: evidence based; benefits outweigh harms. Evidence
quality: low. Strength of recommendation: weak.
This recommendation is based on a subgroup of participants in
IBCSG23-01.Ninepercentoftheparticipantsineacharmunderwent
mastectomy(ALND,nϭ44;noALND,nϭ42).Inthestudyanalyses
by subgroup, the results by type of surgery showed a lower risk of
eventswithnoALNDandBCS(Ϯradiationtherapy).Adverseevents,
QOL, and performance were not reported.
This recommendation is based on one subgroup of one study,
involving a small number of participants. Adverse events were greater
with ALND. There are currently conflicting data. There may be re-
search in the future that could further inform this recommendation.
CLINICAL QUESTION 3
What is the role of SNB in special circumstances in clinical practice?
Note: Because of lack of evidence in many areas, the scope of this
section was narrowed to the following circumstances. Recommenda-
tionsfrom2005areavailableinDataSupplement7.Theserecommen-
dations are limited by the insufficiency and paucity of data.
RECOMMENDATION 3.1: MULTICENTRIC
Clinicians may offer SNB for women who have operable breast
cancer and the following circumstance: multicentric tumors. Type:
evidence based; benefits outweigh harms. Evidence quality: interme-
diate. Strength of recommendation: moderate.
For the question of patients with multicentric tumors, the sys-
tematic review found five observational studies meeting the inclusion
criteria. One study reported on survival and axillary recurrence; the
results were not statistically significant. One reported on survival or
DFS, two on recurrence, and three on performance. No significant
differences were reported. One was a substudy of the ALMANAC trial
(which was included as an RCT informing Clinical Question 1), in
which all patients underwent SNB. There were no significant differ-
ences for either FNR or number of failed localizations for those with
multifocal metastases.19
In another substudy of ALMANAC,28
there
were no significant differences in performance. There is one registry
study examining risk factors for axillary recurrence. The investigators
divided patients with tumor-free SNB into four subgroups (small
unifocal, large unifocal, small multifocal, and large multifocal [metas-
tases]). There were axillary recurrences in 0.4% of the patients with
small unifocal, 1.6% of those with small multifocal, and 0% of those
with large unifocal or large multifocal tumors.29
Inanotherstudy,overallaccuracywassimilarbetweenmulticen-
tric and unicentric groups; the FNR was lower for the multicentric
group. NPV was 93.3% for multicentric and 97.9% for unicentric.30
In the observational data reviewed, no meaningful differences
were observed between studies using the terminology of multicentric
or multifocal. The harms of omitting ALND do not seem to outweigh
the benefits. Therefore, the Update Committee suggests that women
with multicentric tumors be evaluated for SNB by the criteria in
Recommendations 1 and 2.
RECOMMENDATION 3.2: DUCTAL CARCINOMA
IN SITU
cancer and the following circumstance: ductal carcinoma in situ
(DCIS), when mastectomy is performed. Type: informal consensus;
benefits outweigh harms. Evidence quality: insufficient. Strength of
recommendation: weak.
Clinicians may perform SNB for DCIS diagnosed by minimally
invasivebreastbiopsy:one,whenmastectomyisplanned,becausethis
precludes subsequent SNB at a second operation; two, when physical
examination or imaging shows a mass lesion highly suggestive of
invasive cancer; or three, when the area of DCIS by imaging is large
(Ն 5 cm).
DCIS is characterized by proliferation of ductal epithelium with-
out penetration or invasion through the ductal basement membrane.
DCIS may be present as a component of an invasive cancer, or it may
existwithoutanyinvasivecancer.Ingeneral,cliniciansagreethatpure
DCIS without a coexisting invasive cancer cannot invade lymphatics
and spread to regional nodes. However, because of the sampling error
of minimally invasive biopsies, a substantial fraction of women
identified with pure DCIS on a core-needle/vacuum-assisted min-
imally invasive biopsy prove to have some component of invasive
cancer at surgical resection.31
However, there is currently no vali-
dated method to predict which patients will have invasive cancer in
this setting. This has been used by some to justify performing SNB
in all women with DCIS identified by core-needle/vacuum-assisted
minimally invasive breast biopsy. Retrospective series show that a
small percent have node metastases identified. However, a large
majority of these are classified as micrometastases or clusters of
isolated tumor cells (Ͻ 0.2 mm). Other data as reviewed in our
update show that SNB can be performed in women with a prior
surgical excision in the breast with success, and accuracy rates are
equal to those in women with no prior breast excision.
There were no studies that met criteria for evaluation of SNB for
patients with DCIS, as confirmed by other recent systematic re-
views.1,2
The rate of identification of metastatic SLNs defined in the

systematic reviews for patients proving to have pure DCIS on final
resection is 0.9% for pN1 and 1.5% for pN1mic (micrometastases).
ForwomenwithaminimallyinvasivebiopsyshowingDCISwho
arebeingtreatedwithBCS,thereisnoevidencetosupportperforming
SNB (see Recommendation 4.3). Performing SNB places patients at
risk for long-term complications including permanent lymphedema.
SNB may be performed as a separate second procedure in the women
in whom invasive cancer is found (reported in 10% to 20% of cases
overall, approximately half of which are limited to microinvasive
cancer). Exceptions may include cases where breast imaging or phys-
ical examination show an obvious mass characteristic of invasive can-
cer or a large area of calcification without a mass (eg, Ն 5 cm) where
the probability of finding invasive cancer on the resection specimen is
high. In addition, when mastectomy is performed for DCIS, it may be
warranted to perform SNB because of the possibility of finding an
invasive cancer in the resected breast, and the disruption of the lym-
phatics by the mastectomy may preclude a subsequent SNB. These
recommendations are primarily based on retrospective data. There-
fore, the Update Committee does not endorse routine SNB for pa-
tients with DCIS undergoing BCS.
RECOMMENDATION 3.3: PRIOR SURGERY
cancer and the following circumstance: prior breast and/or axillary
surgery. Type: evidence based; benefits outweigh harms. Evidence
quality: intermediate. Strength of recommendation: strong.
The systematic review found two observational studies meeting
the inclusion criteria. These studies did not report survival or DFS.
One study reported recurrence and found a slightly higher recurrence
rate for patients who had undergone prior biopsy. Both studies re-
ported performance and did not find differences in those outcomes.
The first was a nonrandomized study that had two temporal
phases, each including two groups (those with nonpalpable lesions
and those with prior diagnostic biopsy). Distant recurrence for those
with metastatic SLNs was as follows: prior biopsy, 5%; nonpalpable
lesion, 1%. For patients with tumor-free SLNs, distant recurrence was
as follows: prior biopsy, 2.0%; nonpalpable lesion, 0.5%. Axillary
recurrence for those who had undergone prior surgery was zero in
boththosewithmetastaticSLNsandthosewithtumor-freeSLNs.The
SLNdetectionrateforthosehavingundergonepriorsurgerywas96%
versus 95%, and the FNR was 10% versus 5.6%.32
The second study
was a nonrandomized study that included two groups: one group had
undergone prior excisional biopsies, and the comparison group had
undergone diagnostic core biopsies. Overall accuracy and sensitivity
was 100% in the first group, and there were no false negatives.33
Although there are no randomized data or other additional evi-
dence that meet the eligibility criteria for this guideline update, the
retrospective data are consistent with the feasibility and acceptable
accuracy of performing SLN biopsy in patients who have undergone
prior nononcologic breast/axillary surgery.
RECOMMENDATION 3.4: PREOPERATIVE/
NEOADJUVANT SYSTEMIC THERAPY
Clinicians may offer SNB for women who have operable
breast cancer and the following circumstance: preoperative/
neoadjuvant systemic therapy (NACT). Type: evidence based;
benefits outweigh harms. Evidence quality: intermediate.
Strength of recommendation: moderate.
SNB may be offered before or after NACT, but the procedure
seems less accurate after NACT.
There were three cohort studies in the ASCO systematic review
on preoperative systemic therapy and/or NACT. None reported sur-
vival/mortality, and one reported recurrence; the other data were on
performance. Most of the studies did not show statistically significant
differences in the reported outcomes between those who received
NACT and those who did not,34,35
including FNR in the two studies
that reported it.34-36
The analysis of the first study excluded patients who had SNB
only (although included them in the study). Overall accuracy for
those who had received preoperative chemotherapy was 95.9%
versus 92.6% for those who had not received preoperative chemo-
therapy. Among patients whose SLNs were successfully identified,
the overall accuracy rate was 93.7%. The FNR was not significantly
different. For those who received preoperative chemotherapy, the
NPV was 86.8%.34
There was a second smaller study of patients with locally ad-
vanced breast cancer. The comparison group (patients with early-
stage breast cancer) was from a previous RCT. The FNR for SNB after
NACT was 5.2%. The third study was small and retrospective/pro-
spective. The sole recurrence information it reported was distant re-
currence in one of 52 patients who had received neoadjuvant
chemotherapy.Themediandetectionratewasnonsignificantbetween
those who had not received neoadjuvant chemotherapy and those
who had received it. The only statistically significant result was the
number of lymph nodes removed, which was statistically significantly
greater in the non-NACT group.37
SNB may be offered before or after NACT, but the FNR is higher
afterward, and therefore, the procedure seems less accurate after
NACT.Theoutcomeforpatientswhohavemetastaticnodesthatthen
become negative has never been investigated. There were some other
studies that were not included in the systematic review and, therefore,
donotsupporttherecommendationbutareselectivelydiscussedhere.
One study did not fit the ASCO systematic review criteria, be-
causeitdidnotcompareparticipantswithandwithoutNACT.Aspart
oftheNSABPB27trialofNACTinparticipantswithclinicalstageIIor
III breast cancer, axillary dissection was required for all patients. The
dates of this study coincided with ongoing studies from NSABP and
ACOSOG of SNB in patients with clinical node tumor-free breast
cancer.Thetechniquewasnotstandardized,anditwasnotincludedin
the actual B27 study. Although SNB was not a component of the B27
study, the NSABP determined that 428 participants had SNB before
the required ALND at the treating center. The NSABP elected to
report the collective findings. However, the findings are limited by the
Lyman et al

factthatthetechniqueofSNBwasselectedbythetreatingsurgeonand
was not consistent (radioactive colloid alone, 15%; lymphazurin
alone, 30%; both, 55%). At least one SLN was identified in 85% of
patientcases.Among343patientswithbothSNBandALND,125had
metastatic nodes. Among those with tumor-free SLNs, 15 had meta-
static nonsentinel nodes (FNR, 10.7%).38
The benefits outweigh the harms in a given patient, because the
patienthasalreadyreceivedsystemictherapy,andtheimpactofafalse
negative is unlikely to lead to omission of radiation therapy. Cells
remaining in the SLNs after chemotherapy may be chemoresistant,
and postoperative chemotherapy is variable and often not pursued.
Radiation to the axilla may reduce the risk but is variably applied. For
patients with metastatic nodes before NACT, the FNR with SNB after
treatment may range from 10% to 30%, which, in the view of the
Update Committee, is unacceptable. This may result in understaging
and undertreatment of such patients. The SLN removed may not be
the same node previously biopsied and found to be metastatic. The
SENTINA (Sentinel Neoadjuvant) trial observed an FNR of 14.2%
(and much higher rates if only one or two SLNs were removed).39
More than half of patients who became clinically tumor free after
NACT still had metastatic nodes pathologically. For example, the
ACOSOG Z1071 trial found FNRs Ͼ 12% when only Ն two SLNs
were removed.40
There were FNRs of 31% if only one SLN was re-
moved and 20% for single-agent lymphatic mapping (isotope or dye
alone). Because of the publication dates of the reports, these studies
were not included in the systematic review.
For patients who have received NACT and are considering un-
dergoing SNB (Ϯ ALND), the most important measure of outcome is
axillary local recurrence. The Update Committee urges caution about
SNB after NACT because of the fact that no studies to date have
reported a positive result in axillary local recurrence.
In the expert opinion of the Update Committee, SNB is not
recommended in patients with T4d/inflammatory breast cancer who
have received NACT (regardless of patients’ clinical response to
NACT), and data are insufficient to recommend SNB in patients with
T4abcbreastcancerwhosecancerhasbeenclinicallydownstagedafter
receiving NACT.
In addition, SLN biopsy after NACT is associated with a learning
curve and surgical expertise.41
Lastly, decisions regarding the use of
locoregional radiation therapy after NACT may be influenced by the
histopathologic pre- as well as post-NACT nodal status. In the expert
opinion of the Update Committee, data are presently insufficient, but
the committee will take under consideration any data forthcoming
regarding SNB in patients who have node metastases at presentation
by pretreatment axillary FNA biopsy and are planning to re-
ceive NACT.
OTHER SPECIAL CIRCUMSTANCES
RECOMMENDATION 4.1: LARGE AND LOCALLY
ADVANCED INVASIVE TUMORS (T3/T4)
There are insufficient data to change the 2005 recommendation
that clinicians should not perform SNB for women who have early-
stage breast cancer and have the following circumstance: large or
locally advanced invasive breast cancer (tumor size T3/T4). Type:
informalconsensus.Evidencequality:insufficient.Strengthofrecom-
mendation: weak.
There was one study found. The single small study meeting the
inclusion criteria included 64 patients with locally advanced breast
cancer. The comparison group (patients with early-stage breast can-
cer)wasfromapreviousRCT.Theoverallaccuracyresultswere96.7%
for patients with locally advanced breast cancer and 93.0% for those
with early-stage breast cancer. Other results included FNRs (locally
advanced, 5.1%; early stage, 5.8%), NPV (locally advanced, 91.3%;
early stage, 91.1%), and sensitivity (locally advanced, 88.1%; early
stage, 77.1%). It should be noted that because the control group was
retrospective, it was on the borderline of the inclusion criteria. This
studywasalsorelevanttothepreoperative/neoadjuvantsystemicther-
apy question (Recommendation 3.4).36
There were no new data found to support offering SNB to
women with T3/T4d/inflammatory breast cancer that would change
the 2005 recommendation. There are also no data to support SNB for
patients with T4a/T4b/T4c breast cancer who will undergo primary
surgery, because their clinical teams will likely administer primary
systemic therapy/NACT, and the decision regarding SLN biopsy
would be subject to the interpretation of data on primary sys-
temic therapy/NACT.
RECOMMENDATION 4.2
stage breast cancer and have the following circumstance: inflamma-
tory breast cancer. Type: informal consensus. Evidence quality:
insufficient. Strength of recommendation: weak.
RECOMMENDATION 4.3
stage breast cancer and the following circumstance: DCIS, when BCS
is planned. Type: informal consensus. Evidence quality: insufficient.
Strength of recommendation: strong.
RECOMMENDATION 4.4
stage breast cancer and have the following circumstance: pregnancy.
Type: informal consensus. Evidence quality: insufficient. Strength of
recommendation: weak.
There were insufficient data to change some of the 2005 rec-
ommendations regarding performing SNB in several of the special
circumstances, including women with early-stage breast cancer
who have smaller tumors (T1/T2) and the presence of suspicious
palpable axillary lymph nodes. Neither circumstance was included
in the current systematic review. This update deleted a recommen-
dation for patients who had undergone prior nononcologic breast
surgery or axillary surgery because of insufficient data to in-
form recommendations.
Age should not be a factor when clinicians and patients are
deciding whether to pursue SNB (Ϯ ALND). There are insufficient
data to show there are any differences in outcome by chronologic age.
There are no studies that meet the criteria for inclusion in this guide-
line addressing the questions of the accuracy, safety, and value of SNB

onolderwomen.ManystudiesofSNBcitedinthisguidelineincluded
some older women. There is no reason to expect that SNB is not
equally accurate in older women than in the general population of
women included in these studies. As in all women with breast cancer,
the need for axillary surgical staging with SNB or axillary dissection
should be defined by: one, the requirement for lymph node staging to
determine subsequent adjuvant therapies; two, the short- and long-
term risks of the surgery; and three, the patient’s objectives and intent
for therapy.
Body mass index/body-surface area should similarly not be fac-
tors when clinicians and patients are deciding whether to pursue SNB
(ϮALND).Becausetherewereinsufficientdatatoindicatethesewere
important clinical factors, they were not included in the final recom-
mendations for this update.
Currently, there is controversy regarding the optimal manage-
mentwithradiationtherapyofpatientswithmetastaticSLNsonSNB.
Almost all of the currently available data on omitting axillary dissec-
tion in patients with metastatic SLNs come from patients managed
with BCS followed by conventionally fractionated whole-breast radi-
ation therapy delivered in the supine position who have not received
neoadjuvant systemic therapy. If more published evidence becomes
availableregardingtheroleofradiationtherapy,theUpdateCommit-
tee or a subset of the committee may consider including it in any
future updates of this guideline.
SPECIAL COMMENTARY
Occult Metastases, Isolated Tumor Cells,
and Micrometastases
NSABP B32 included a double-blind cohort study of occult me-
tastasesforallpatientswithtumor-freeSLNsenrolledontotheRCT.14
Occult metastases were isolated tumor cells (ITCs) or micrometasta-
ses, and rarely macrometastases, that were not detected on initial
pathology and not used for clinical management but were detected
with further evaluation. Detection of occult metastases is a method to
test the clinical value of deeper levels and immunohistochemistry
(IHC). Occult metastases are usually found only in deeper-cut HE
sections, IHC stains, or molecular testing of an SLN thought to be
tumor free based on the initial-level HE section.
The study detected occult metastases in 15.9% of 3,887 patients.
Observed differences in patients with or without occult metastases for
OS (1.2%; P ϭ .03), DFS (2.8%; P ϭ .02), and distant disease–free
interval (2.8%; P ϭ .04) were small, and although statistically signifi-
cant, they were not clinically significant. The corresponding adjusted
hazard ratios for death, any outcome event, and distant disease were
1.40(95%CI,1.05to1.86),1.31(95%CI,1.07to1.60),and1.30(95%
CI,1.02to1.66),respectively.Five-yearKaplan-MeierestimatesofOS
among patients in whom occult metastases were detected and those
without detectable metastases were 94.6% and 95.8%, respectively.
Identification of occult metastases did not predict locoregional recur-
rence, DFS, or OS.
ACOSOG Z0010, a double-blind registration cohort study, also
evaluated occult metastases. One additional level and IHC were per-
formed, compared with two widely spaced levels and IHC on NSABP
B32. Occult metastases were detected in 10.5% of 3,326 SLN speci-
mens.25
Thistrialpermittedtheinstitutionalpathologiststogetoneor
two deeper-cut HE levels in addition to the first cut off the top of the
paraffinblock.CytokeratinIHCwasnotallowedforclinicaldiagnosis.
Thesedifferencesmayexplainwhytheoccultmetastasisdetectionrate
in the central laboratory was lower in the Z0010 trial compared with
theB32trial.Nosignificantdifferencewasdetectedfor5-yearOS(Pϭ
.64) or DFS (P ϭ .82) between patients with and without IHC-
detected occult metastases. Neither B32 nor Z0010 support routine
useoflevelsorIHCfordetectionofITCsormicrometastasesthatmay
bepresentinSLNparaffinblocksthataretumorfreeoninitialpathol-
ogy evaluation of a single routinely stained section of the SLN. IBCSG
23-01 provides further evidence for this conclusion.12
All SLNs were
evaluated with multiple levels entirely through the SLN, and patients
with Ն one SLN with micrometastasis (Յ 2.0 mm) were randomly
assignedtoaxillarydissectionornofurtheraxillarysurgery.Therewas
no statistical difference in 5-year DFS between the groups.
Pathology
The update of this systematic review did not include pathology
and/or pathology evaluation. Therefore, the following is based on the
expert opinion of the Update Committee. Different studies have used
different methods to evaluate SLNs and, thus, different criteria to
define those with metastatic versus tumor-free nodes. Pathologists
may have determined a tumor-free node with IHC5-9,11
or may have
determined a tumor-free node without routine IHC.12,16
When IHC
wasused,thisresultedinahigherpercentageofnodesratedaspositive
(or metastatic) and of the inclusion of patients in the node-positive
group with two to three micrometastases or ITC clusters as deter-
mined by either HE or IHC. This may have diluted apparent outcome
differences between ALND and no ALND in some studies. The differ-
ences in method and definition among studies were largely regional
(eg, US-based studies did not use IHC; European- and Australian-
based studies used IHC).
As recommended in this guideline, SNB is the recommended
surgical procedure for evaluation of clinically tumor-free regional
nodes in patients with breast cancer, barring other exclusions. Clini-
cians, pathologists, and patients should be aware of the significance of
identifying metastases in lymph nodes, even single cancer cells, as well
as the reality that small metastases will be missed. Presence or absence
of nodal metastases is the basis on which treatment decisions are
made. In the expert opinion of the authors, pathologists, as part of
their standard analysis, should quantify nodal tumor burden. Further
discussion of the pathologic evaluation of SLNs from patients with
breast cancer is available in Appendix 2 (online only).
PATIENT AND CLINICIAN COMMUNICATION
For SNB, as in all decision-making processes, appropriate communi-
cation is a critical component for the physician-patient relationship
and for optimal patient compliance and outcome. Consideration of
the patient’s perspective, setting realistic expectations by discussing
potential benefits and harms associated with SNB, explaining poten-
tial outcomes, and taking the time to understand what QOL means to
the individual patient are key components of this communication.
With this as the guiding standard of practice, the Update Com-
mittee continues to recommend that, as with any medical procedure,
written informed consent be obtained from all patients before SNB.
The benefits and harms of the procedure, including the potential for a
false-negative result, should be explained to the patient and include
Lyman et al

evidence-based information. Written patient educational materials
should provide accurate information on the risk of complications,
contraindications for the procedure, the need for a multidisciplinary
team (surgeon, nuclear medicine technician, and pathologist), the
potential costs (which may be offset by fewer complications and less
follow-up care), the current status of long-term survival data, the risk
of radiation exposure, and the follow-up protocols for each proce-
dure. A comparison of the data in an understandable format will help
to clarify some of the issues for patients making treatment choices.
HEALTH DISPARITIES
Although ASCO clinical practice guidelines represent expert recom-
mendations on the best practices in disease management to provide
the highest level of cancer care, it is important to note that many
patients have limited access to medical care. Racial and ethnic dispar-
ities in health care contribute significantly to this problem in the
United States. Minority racial/ethnic patients with cancer dispropor-
tionately experience comorbidities; they experience more substantial
obstacles to receiving care, are more likely to be uninsured, and are at
greaterriskofreceivingcareofpoorqualitythanotherAmericans.42-45
Manyotherpatientslackaccesstocarebecauseoftheirgeographyand
distance from appropriate treatment facilities.
A literature search, although not systematic, was conducted to
find literature addressing health disparities and SNB for patients with
early-stagebreastcancer.Sixrelevantstudieswerefound.Someobser-
vational studies, including studies of SEER data, have indicated that
women of color, including African American, Asians, and Hispanics,
arelesslikelytoundergoSNBthanwhitewomen.42-46
Forexample,in
an analysis of SEER data from 2000 to 2005 by Shah et al,47
women
with DCIS treated with mastectomy who were of Asian or Hispanic
race/ethnicity were less likely to have undergone SNB. In a SEER/
MedicarestudyofwomenundergoingBCS,AfricanAmericanand/or
elderly women and those with lower socioeconomic were less likely to
undergo SNB, and those associated with a National Cancer Institute
cooperative group were more likely to undergo SNB.48
In a third
study, not undergoing SNB was associated with urbanity, as well as
other racial/ethnic and socioeconomic factors. A fourth study found
that the patients in the National Cancer Database from 2003 to 2005
ageՆ73yearswerethreetimesaslikelynottoundergoSNBorALND,
aswellasshowingdisparitiesbyracial/ethnicandinsurancestatus.49
A
fifth study found a 33% difference in use of SNB between white and
African American women (P ϭ .026).46
These findings occur in the
context of health disparities that are well characterized in women with
breast cancer.50
Awareness of these disparities in access to care should
be considered in the context of this clinical practice guideline, and
healthcareprovidersshouldstrivetodeliverthehighestlevelofcancer
care to these vulnerable populations.
MULTIPLE CHRONIC CONDITIONS
Creating evidence-based recommendations to inform treatment of
patients with additional chronic conditions, a situation in which the
patient may have Ն two such conditions—referred to as multiple
chronic conditions (MCCs)—is challenging. Patients with MCCs are
a complex and heterogeneous population, making it difficult to ac-
count for all of the possible permutations to develop specific recom-
mendations for care. In addition, the best available evidence for
treating index conditions, such as cancer, is often from clinical trials,
where study selection criteria may exclude these patients to avoid
potential interaction effects or confounding of results associated with
MCCs. As a result, the reliability of outcome data from these studies
maybelimited,therebycreatingconstraintsforexpertgroupstomake
recommendations for care in this heterogeneous patient population.
Because many patients for whom guideline recommendations
apply present with MCCs, any management plan needs to take into
account the complexity and uncertainty created by the presence of
MCCs and highlight the importance of shared decision making
around guideline use and implementation. Therefore, in consider-
ation of recommended care for the target index condition, clinicians
should review all other chronic conditions present in the patient and
take those conditions into account when formulating the treatment
and follow-up plan (common chronic conditions for patients with
breast cancer are listed in Data Supplement 6).
Taking these considerations into account, practice guidelines
should provide information on how to apply the recommendations
for patients with MCCs, perhaps as a qualifying statement for recom-
mended care. This may mean that some or all of the recommended
care options are modified or not applied, as determined by best prac-
tice in consideration of any MCC.
EXTERNAL REVIEW
Thepathologyappendixwassubmittedtotwoexternalreviewerswith
content expertise, and it was agreed it would be useful in practice.
ReviewcommentswerereviewedbyD.L.W.andR.R.T.andintegrated
into the final manuscript.
GUIDELINE IMPLEMENTATION
ASCO guidelines are developed to be implemented in a variety of
health settings. Barriers to implementation and application of the
guideline recommendations include the need to increase awareness
among front-line practitioners and cancer survivors and also the need
to provide adequate services in the face of limited resources. The
guideline Bottom Line was designed to facilitate implementation of
recommendations. This guideline will be distributed widely through
the ASCO Practice Guideline Implementation Network and other
ASCO communications. ASCO guidelines are posted on the ASCO
Web site and most often published in Journal of Clinical Oncology
(JCO) and Journal of Oncology Practice.
Given the multidisciplinary care discussed in this guideline and
the importance of sharing the update with the many relevant stake-
holders, it is suggested that community oncologists, surgical oncolo-
gists, and radiation oncologists as well as patient navigators and
academic, community, and hospital-based cancer centers consider
these guidelines. In addition, given that the majority of US cancer
programshavecancertumorboardsorcontinuingmedicaleducation
activities that include the many clinicians treating breast cancer, we
encourage those programs to distribute and stimulate discussion of
this guideline update. In expanding outreach of ASCO guidelines
through the national tumor board system, we hope to speed the

sharing of this update as well as to stimulate coordinated multidisci-
plinary care decisions among medical oncologists, radiation oncolo-
gists, and surgical oncologists as well as patients, their advocates, and
cancer program leaders. The American College of Surgeons, which
accredits most US cancer programs, has included review of National
Comprehensive Cancer Network guidelines for the diagnosis and
treatment of cancer as quality measures in the past few years. Discus-
sion of including ASCO guidelines and updates as part of this process
would further increase the review and discussion of ASCO guidelines
and likely speed the uptake of newly evaluated studies and guideline
updates that can improve the quality of cancer care for patients.
LIMITATIONS OF RESEARCH AND FUTURE DIRECTIONS
Datawereinsufficienttomakerecommendationsortorateallrecom-
mendations as high on several of the categories of patients in special
circumstances. These include patients with DCIS, T1/T2 tumors,
T3/T4 tumors, inflammatory breast cancer, and T4d/inflammatory
breast cancer who have received NACT; pregnant patients; SLN bi-
opsy in patients with T4abc breast cancer whose cancer has been
clinically downstaged after receiving NACT; SLN biopsy in patients
who have node metastases at presentation by pretreatment axillary
FNA biopsy and are planning to receive NACT; and patients with
suspicious palpable axillary lymph nodes. Ongoing RCTs on NACT
include NSABP B51 (ClinicalTrials.gov identifier: NCT01872975)
and Alliance 11202.
Data are insufficient to address whether patients with FNA-
positive results can undergo SNB (under the assumption that resected
SLNs represent FNA-biopsied nodes) and then avoid ALND after
resection of the metastatic SLNs. In addition, additional data on SNB
and mastectomy, the role of age, and communicating the choices to
patients are needed, in addition to data on the role of radiation ther-
apy.Moreresearchisneededandencouragedonthepotentialroleand
limitations of SNB in these settings.
ASCO believes that cancer clinical trials are vital to inform med-
ical decisions and improve cancer care and that all patients should
have the opportunity to participate.
ADDITIONAL RESOURCES
This guideline was published in JCO. Additional information, includ-
ing an Appendix on Pathology, a Data Supplement with additional
evidence tables, a Methodology Supplement, slide sets, clinical tools,
and resources, is available at www.asco.org/guidelines/breastsnb. Pa-
tient information is available there and at www.cancer.net.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Administrative support: Sarah Temin
Manuscript writing: All authors
Final approval of manuscript: All authors
REFERENCES
1. Veronesi U, Paganelli G, Viale G, et al: A
randomized comparison of sentinel-node biopsy
with routine axillary dissection in breast cancer.
N Engl J Med 349:546-553, 2003
2. Shiffman RN, Michel G, Rosenfeld RM, et al:
Building better guidelines with BRIDGE-Wiz: Devel-
opment and evaluation of a software assistant to
promote clarity, transparency, and implementability.
J Am Med Inform Assoc 19:94-101, 2012
3. Canavese G, Catturich A, Vecchio C, et al:
Sentinel node biopsy compared with complete axil-
lary dissection for staging early breast cancer with
clinically negative lymph nodes: Results of random-
ized trial. Ann Oncol 20:1001-1007, 2009
4. Giuliano AE, Hunt KK, Ballman KV, et al:
Axillary dissection vs no axillary dissection in
women with invasive breast cancer and sentinel
node metastasis: A randomized clinical trial. JAMA
305:569-575, 2011
5. Mansel RE, Fallowfield L, Kissin M, et al:
Randomized multicenter trial of sentinel node bi-
opsy versus standard axillary treatment in operable
breast cancer: The ALMANAC trial. J Natl Cancer
Inst 98:599-609, 2006
6. Zavagno G, De Salvo GL, Scalco G, et al: A
randomized clinical trial on sentinel lymph node
biopsy versus axillary lymph node dissection in
breast cancer: Results of the Sentinella/GIVOM trial.
Ann Surg 247:207-213, 2008
7. Smith MJ, Gill PG, Wetzig N, et al: Comparing
patients’ and clinicians’ assessment of outcomes in
a randomised trial of sentinel node biopsy for breast
cancer (the RACS SNAC trial). Breast Cancer Res
Treat 117:99-109, 2009
8. Ung OA: Australasian experience and trials in
sentinel lymph node biopsy: The RACS SNAC trial.
Asian J Surg 27:284-290, 2004
9. Veronesi U, Viale G, Paganelli G, et al: Senti-
nel lymph node biopsy in breast cancer: Ten-year
results of a randomized controlled study. Ann Surg
251:595-600, 2010
10. Veronesi U, Paganelli G, Viale G, et al:
Sentinel-lymph-node biopsy as a staging procedure
in breast cancer: Update of a randomised controlled
study. Lancet Oncol 7:983-990, 2006
11. Purushotham AD, Upponi S, Klevesath MB, et
al: Morbidity after sentinel lymph node biopsy in
primary breast cancer: Results from a randomized
controlled trial. J Clin Oncol 23:4312-4321, 2005
12. Galimberti V, Cole BF, Zurrida S, et al: Axillary
dissection versus no axillary dissection in patients
with sentinel-node micrometastases (IBCSG 23-01):
A phase 3 randomised controlled trial. Lancet Oncol
14:297-305, 2013
13. Krag DN, Anderson SJ, Julian TB, et al:
Sentinel-lymph-node resection compared with con-
ventional axillary-lymph-node dissection in clinically
node-negative patients with breast cancer: Overall
survival findings from the NSABP B-32 randomised
phase 3 trial. Lancet Oncol 11:927-933, 2010
14. Weaver DL, Ashikaga T, Krag DN, et al: Effect
of occult metastases on survival in node-negative
breast cancer. N Engl J Med 364:412-421, 2011
15. Lyman GH, Giuliano AE, Somerfield MR, et al:
American Society of Clinical Oncology guideline
recommendations for sentinel lymph node biopsy in
early-stage breast cancer. J Clin Oncol 23:7703-
7720, 2005
16. Krag DN, Anderson SJ, Julian TB, et al: Tech-
nical outcomes of sentinel-lymph-node resection
and conventional axillary-lymph-node dissection in
patients with clinically node-negative breast cancer:
Results from the NSABP B-32 randomised phase III
trial. Lancet Oncol 8:881-888, 2007
17. Harlow SP, Krag DN, Julian TB, et al: Preran-
domization Surgical Training for the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-32
trial: A randomized phase III clinical trial to compare
sentinel node resection to conventional axillary dis-
section in clinically node-negative breast cancer.
Ann Surg 241:48-54, 2005
18. Fleissig A, Fallowfield LJ, Langridge CI, et al:
Post-operative arm morbidity and quality of life:
Results of the ALMANAC randomised trial compar-
ing sentinel node biopsy with standard axillary treat-
ment in the management of patients with early
breast cancer. Breast Cancer Res Treat 95:279-293,
2006
19. Goyal A, Newcombe RG, Chhabra A, et al:
Factors affecting failed localisation and false-
negative rates of sentinel node biopsy in breast
cancer: Results of the ALMANAC validation phase.
Breast Cancer Res Treat 99:203-208, 2006
20. Del Bianco P, Zavagno G, Burelli P, et al:
Morbidity comparison of sentinel lymph node biopsy
versus conventional axillary lymph node dissection
for breast cancer patients: Results of the sentinella-
GIVOM Italian randomised clinical trial. Eur J Surg
Oncol 34:508-513, 2008
21. Zavagno G, Del Bianco P, Koussis H, et al:
Clinical impact of false-negative sentinel lymph
Lyman et al

nodes in breast cancer. Eur J Surg Oncol 34:620-
625, 2008
22. Bochner MA, Kollias J, Gill PG, et al: Implica-
tion of intraoperative sentinel node imprint cytology
for consent in the SNAC trial. ANZ J Surg 74:105-
107, 2004
23. Gill PG: Sentinel lymph node biopsy versus
axillary clearance in operable breast cancer: The
RACS SNAC trial, a multicenter randomized trial of
the Royal Australian College of Surgeons (RACS)
Section of Breast Surgery, in collaboration with the
National Health and Medical Research Council Clin-
ical Trials Center. Ann Surg Oncol 11:216S-221S,
2004 (suppl)
24. Ashikaga T, Krag DN, Land SR, et al: Morbidity
results from the NSABP B-32 trial comparing senti-
nel lymph node dissection versus axillary dissection.
J Surg Oncol 102:111-118, 2010
25. Wilke LG, McCall LM, Posther KE, et al:
Surgical complications associated with sentinel
lymph node biopsy: Results from a prospective
international cooperative group trial. Ann Surg Oncol
13:491-500, 2006
26. Lucci A, McCall LM, Beitsch PD, et al: Surgical
complications associated with sentinel lymph node
dissection (SLND) plus axillary lymph node dissec-
tion compared with SLND alone in the American
College of Surgeons Oncology Group Trial Z0011.
J Clin Oncol 25:3657-3663, 2007
27. Olson JA Jr, McCall LM, Beitsch P, et al:
Impact of immediate versus delayed axillary node
dissection on surgical outcomes in breast cancer
patients with positive sentinel nodes: Results from
American College of Surgeons Oncology Group Tri-
als Z0010 and Z0011. J Clin Oncol 26:3530-3535,
2008
28. Goyal A, Horgan K, Kissin M, et al: Sentinel
lymph node biopsy in male breast cancer patients.
Eur J Surg Oncol 30:480-483, 2004
29. Meretoja TJ, Leidenius MH, Heikkila¨ PS, et al:
Sentinel node biopsy in breast cancer patients with
large or multifocal tumors. Ann Surg Oncol 16:1148-
1155, 2009
30. Knauer M, Konstantiniuk P, Haid A, et al:
Multicentric breast cancer: A new indication for
sentinel node biopsy—A multi-institutional validation
study. J Clin Oncol 24:3374-3380, 2006
31. Virnig BA, Tuttle TM, Shamliyan T, et al:
Ductal carcinoma in situ of the breast: A systematic
review of incidence, treatment, and outcomes.
J Natl Cancer Inst 102:170-178, 2010
32. Celebioglu F, Frisell J, Danielsson R, et al:
Sentinel node biopsy in non-palpable breast cancer
and in patients with a previous diagnostic excision.
Eur J Surg Oncol 33:276-280, 2007
33. Heuts EM, van der Ent FW, Kengen RA, et al:
Results of sentinel node biopsy not affected by
previous excisional biopsy. Eur J Surg Oncol 32:278-
281, 2006
34. Lee S, Kim EY, Kang SH, et al: Sentinel node
identiﬁcation rate, but not accuracy, is signiﬁcantly
decreased after pre-operative chemotherapy in axil-
lary node-positive breast cancer patients. Breast
Cancer Res Treat 102:283-288, 2007
35. Patel NA, Piper G, Patel JA, et al: Accurate
axillary nodal staging can be achieved after neoad-
juvant therapy for locally advanced breast cancer.
Am Surg 70:696-699, 2004; discussion 699-700
36. Canavese G, Dozin B, Vecchio C, et al:
Accuracy of sentinel lymph node biopsy after
neo-adjuvant chemotherapy in patients with lo-
cally advanced breast cancer and clinically posi-
tive axillary nodes. Eur J Surg Oncol 37:688-694,
2011
37. Stell VH, Flippo-Morton TS, James Norton H,
et al: Sentinel lymph node biopsy after neo-adjuvant
chemotherapy in breast cancer. Breast J 17:71-74,
2011
38. Mamounas EP, Brown A, Anderson S, et al:
Sentinel node biopsy after neoadjuvant chemother-
apy in breast cancer: Results from National Surgical
Adjuvant Breast and Bowel Project Protocol B-27.
J Clin Oncol 23:2694-2702, 2005
39. Kuehn T, Bauerfeind I, Fehm T, et al: Sentinel-
lymph-node biopsy in patients with breast cancer before
and after neoadjuvant chemotherapy (SENTINA): A pro-
spective, multicentre cohort study. Lancet Oncol 14:609-
618, 2013
40. Boughey JC, Suman VJ, Mittendorf EA, et al:
Sentinellymphnodesurgeryafterneoadjuvantchem-
otherapy in patients with node-positive breast can-
cer: The ACOSOG Z1071 (Alliance) clinical trial.
JAMA 310:1455-1461, 2013
41. Breslin TM, Cohen L, Sahin A, et al: Sentinel
lymph node biopsy is accurate after neoadjuvant
chemotherapy for breast cancer. J Clin Oncol 18:
3480-3486, 2000
42. American Cancer Society: Cancer Facts and
Figures for African Americans 2011-2012. Atlanta,
GA, American Cancer Society, 2011
43. US Department of Health and Human Ser-
vices, Centers for Disease Control and Prevention
and National Cancer Institute: US Cancer Statistics
Working Group: United States Cancer Statistics—
1999-2008 Incidence and Mortality Web-Based Re-
port. www.cdc.gov/uscs
44. Mead H, Cartwright-Smith L, Jones K, et al:
Racial and Ethnic Disparities in U.S. Health Care: A
Chartbook. New York, NY, The Commonwealth
Fund, 2008
45. Howlader N, Noone AM, Krapcho M, et al
(eds): SEER Cancer Statistics Review, 1975-2009
(vintage 2009 populations). Bethesda, MD, National
Cancer Institute, 2012
46. Maloney N, Koch M, Erb D, et al: Impact of
race on breast cancer in lower socioeconomic status
women. Breast J 12:58-62, 2006
47. Shah DR, Canter RJ, Khatri VP, et al: Utiliza-
tion of sentinel lymph node biopsy in patients with
ductal carcinoma in situ undergoing mastectomy.
Ann Surg Oncol 20:24-30, 2013
48. Reeder-Hayes KE, Bainbridge J, Meyer AM,
et al: Race and age disparities in receipt of sentinel
lymph node biopsy for early-stage breast cancer.
Breast Cancer Res Treat 128:863-871, 2011
49. Halpern MT, Chen AY, Marlow NS, et al:
Disparities in receipt of lymph node biopsy among
early-stage female breast cancer patients. Ann Surg
Oncol 16:562-570, 2009
50. Silber JH, Rosenbaum PR, Clark AS, et al:
Characteristics associated with differences in sur-
vival among black and white women with breast
cancer. JAMA 310:389-397, 2013
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ASCO Guideline Update: Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer

ASCO Guideline Update: Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer

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